Effective targeting of RNA polymerase I in treatment-resistant prostate cancer


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Low J., Sirajuddin P., Moubarek M., Agarwal S., Rege A., GÜNER G. , ...Daha Fazla

PROSTATE, cilt.79, sa.16, ss.1837-1851, 2019 (SCI İndekslerine Giren Dergi) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 79 Konu: 16
  • Basım Tarihi: 2019
  • Doi Numarası: 10.1002/pros.23909
  • Dergi Adı: PROSTATE
  • Sayfa Sayıları: ss.1837-1851

Özet

Background Advanced prostate cancers depend on protein synthesis for continued survival and accelerated rates of metabolism for growth. RNA polymerase I (Pol I) is the enzyme responsible for ribosomal RNA (rRNA) transcription and a rate-limiting step for ribosome biogenesis. We have shown using a specific and sensitive RNA probe for the 45S rRNA precursor that rRNA synthesis is increased in prostate adenocarcinoma compared to nonmalignant epithelium. We have introduced a first-in-class Pol I inhibitor, BMH-21, that targets cancer cells of multiple origins, and holds potential for clinical translation. Methods The effect of BMH-21 was tested in prostate cancer cell lines and in prostate cancer xenograft and mouse genetic models. Results We show that BMH-21 inhibits Pol I transcription in metastatic, castration-resistant, and enzalutamide treatment-resistant prostate cancer cell lines. The genetic abrogation of Pol I effectively blocks the growth of prostate cancer cells. Silencing of p53, a pathway activated downstream of Pol I, does not diminish this effect. We find that BMH-21 significantly inhibited tumor growth and reduced the Ki67 proliferation index in an enzalutamide-resistant xenograft tumor model. A decrease in 45S rRNA synthesis demonstrated on-target activity. Furthermore, the Pol I inhibitor significantly inhibited tumor growth and pathology in an aggressive genetically modified Hoxb13-MYC|Hoxb13-Cre|Pten(fl/fl) (BMPC) mouse prostate cancer model. Conclusion Taken together, BMH-21 is a novel promising molecule for the treatment of castration-resistant prostate cancer.